The pituitary gland is attached to a stalk to the region in the base of the brain known as the hypothalamus and has two principal lobes, the anterior lobe and the posterior lobe. The posterior lobe of the pituitary gland stores and passes onto the general circulation system two hormones manufactured in the hypothalamus, i.e., vasopressin and oxytocin. The anterior lobe of the pituitary gland secretes a number of hormones, which are complex protein or glycoprotein molecules, that travel through the bloodstream to various organs and which, in turn, stimulate the secretion into the bloodstream of other hormones from the peripheral organs. In particular, follicle stimulating hormone (FSH) and luteinizing hormone (LH), sometimes referred to as gonadotropins or gonadotropic hormones, are released by the pituitary gland. These hormones, in combination, regulate the functioning of the gonads to produce testosterone in the testes and progesterone and estrogen in the ovaries, and also regulate the production and maturation of gametes.
The release of a hormone by the anterior lobe of the pituitary gland usually requires a prior release of another class of hormones produced by the hypothalamus. Such a hypothalamic hormone acts as a factor that triggers the release of the gonadotropic hormones, particularly LH. The particular hypothalamic hormone which acts as a releasing factor for the gonadotropins LH and FSH is referred to herein as GnRH, wherein RH stands for "releasing hormone" and Gn signifies that gonadotropin hormones are being released. It is sometimes also referred to as LRF and LHRH. GnRH from mammals, e.g. humans, sheep, pigs, cows, rats, etc., has been previously isolated, identified and synthesized.
Mammalian GnRH has been characterized as a decapeptide having the following structure: EQU pGlu--His--Trp--Ser--Tyr--Gly--Leu--Arg--Pro--Gly--NH.sub.2.
Peptides are compounds which contain two or more amino acids in which the carboxyl group of one acid is linked to the amino group of the other acid. The formula for GnRH, as represented above, is in accordance with conventional representation of peptides where the amino group appears to the left and the carboxyl group to the right. The position of the amino groups is identified by numbering the amino groups from left to right. In the case of GnRH, the hydroxyl portion of the carboxyl group at the right-hand end has been replaced with an amino group (NH.sub.2) to give an amide function. The abbreviations for the individual amino acid groups above are conventional and are based on the trivial name of the amino acid: where pGlu is pyroglutamic acid, His is histidine, Trp is tryptophan, Ser is serine, Tyr is tyrosine, Gly is glycine, Leu is leucine, Arg is arginine and Pro is proline. Except for glycine, amino acid residues in the peptides of the invention should be understood to be of the L-configuration unless noted otherwise.
The following abbreviations are used in this application in addition to the usual abbreviations for the trivial names of the more common .alpha.-amino acids:
NVa=norvaline PA1 Orn=ornithine PA1 Ile=isoleucine PA1 Nle=norleucine PA1 Nal=.beta.-naphthyl-Ala PA1 Phg=C-phenylglycine PA1 Abu=2-aminobutyric acid PA1 Chg=2-cyclohexyl Gly PA1 OMe=methylester PA1 OBzl=benzyl ester PA1 tBu=tertiary butyl PA1 BOC=tert-butyloxycarbonyl